Protein kinase C modulators O

Compounds having anti-inflammatory and other activities are disclosed. The compounds are derived from phorboids of the diterpene- and benzolactam-classes.

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Claims

2. A compound of claim 1 wherein S.sub.x E.sub.1, taken together, is selected from the group consisting of:

(i) a moiety selected from the group consisting of dihalomethyl, trihalomethyl, --N.sub.3, --NH.sub.2, --CN, --COOH, --CH.dbd.CHCOOH, --C.tbd.CCOOH, --CSSH, --COSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH, --CH.dbd.NOH, --CH.dbd.CHR.sub.a.sup.a, --C.tbd.C--R.sub.a.sup.a, --CH.sub.2 C.tbd.C--R.sub.a.sup.a, --Si(CH.sub.3).sub.2 OH, --Si(OH).sub.2 CH.sub.3, --Si(CH.sub.3).sub.2 F, --S(CH.sub.3).sub.2 R.sub.a.sup.a, --CH.sub.2 Si(CH.sub.3).sub.2 R.sub.a.sup.a; and.dbd.CHR.sub.a.sup.a; and
(ii) --CH.sub.2 -- or --CH(CH.sub.3)--, to either of which is bonded a moiety selected from the group consisting of --R.sub.a.sup.a, --F, --N.sub.3, --NH.sub.2, --CN, --COOH, --COSH, --CSSH, --Si(CH.sub.3).sub.2 OH, --Si(OH).sub.2 CH.sub.3, --Si(CH.sub.3).sub.2 F, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(R.sub.a.sup.a)OH, --P(.dbd.S)(R.sub.a.sup.a)OH, --P(.dbd.O)(OR.sub.a.sup.a)OH, isomer of --C.sub.6 H.sub.4 CH.sub.2 --T.sup.3, --M--C(.dbd.T.sup.2)--M'--R.sub.a.sup.a, --OCH.sub.2 C(.dbd.O)CH.sub.3, --OCH.sub.2 C(.dbd.NOH)CH.sub.3, the o-, m- or p-isomer of --M--C(.dbd.T.sup.2)--M'--C.sub.6 H.sub.4 --T.sup.3, the o-, m- or p-isomer of --M--C(.dbd.T.sup.2)--M'--C.sub.6 H.sub.4 CH.sub.2 --T.sup.3 and -imidazol-2-yl;

3. A compound of claim 1 wherein P.sub.1 is P.sub.1R: ##STR61## wherein carbons 1 and 2 or carbons 2 and 3 may be joined by a double bond; carbons 5 and 6 or carbons 6 and 7 may be joined by a double bond;

S.sub.x E.sub.1, taken together, may be bonded to carbon 5, 6 or 7;
R.sub.A1 represents not more than 6 identical or different moieties bonded independently via single and/or double bonds to carbons 1, 2 and/or 3, which moieties may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromantic carbon- and/or heteroatom-containing group which groups may form up to two additional rings by connections among themselves and/or to J.sup.1 or R.sub.A4 and which halogen(s) and groups, taken together, contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
R.sub.A3 represents not more than 5 identical or different moieties bonded independently via single and/or double bonds to carbons 5, 6 and/or 7, which moieties may independently be selected from the group consisting of hydrogen halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing groups, which groups may form up to two additional rings by connection to S.sub.x E.sub.1, taken together, and/or J.sup.1 and which halogens and groups, taken together, contain not more than 12 carbon atoms, not more than 8 halogen atoms, and not more than 5 heteroatoms selected from the group selected from oxygen, nitrogen, silicon, phosphorus and sulfur; and
R.sub.A4 represents not more than 9 identical or different moieties bonded independently via single or double bonds to carbons 9, 11, 12, 13 and/or 14, which moieties may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, the group or groups optionally completing 1-3 additional rings through bonds among themselves and/or 1-5 additional rings by connections to the 5-membered ring and its substituent(s), R.sub.A1, which halogens and groups, taken together, include not more than 50 carbon atoms, not more than 24 halogen atoms, and not more than 15 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur.

4. A compound of claim 1 wherein P.sub.1 is P.sub.1I: ##STR62## wherein carbons 1 and 2 or carbons 2 band 3 my be joined by a double bond; carbons 5 and 6 or carbons 6 and 7 may be joined by a double bond;

S.sub.x E.sub.1, taken together, may be bonded to carbon 5, 6 or 7;
R.sub.A2I represents not more than 6 identical or different moieties bonded independently via single and/or double bonds to carbons 1, 2 and/or 3, which moieties may independently be selected from the group consisting of hydrogen halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which groups may form up to two additional rings by connections among themselves and/or to J.sup.1 or R.sub.A4I and which halogens and groups, taken together, contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
R.sub.A3I represents not more than 5 identical or different moieties bonded independently via single and/or double bonds to carbons 5, 6 and/or 7, which moieties may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which groups may form up to two additional rings by connections to S.sub.x E.sub.1, taken together, and/or J.sup.1 and which halogens and groups, taken together, contain not more than 12 carbon atoms, not more than 8 halogen atoms, and not more than 5 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
R.sub.A4I represents not more than 8 identical or different moieties bonded independently via single or double bonds to carbons 11, 12, 13 and/or 14, which moieties may independently be selected from the group consisting of hydrogen halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, the group or groups optionally completing 1-3 additional rings through bonds among themselves and/or 1-5 additional rings by connection to the 5-membered ring and its substituent(s), R.sub.A2I which halogens and groups, taken together, include not more than 50 carbon atoms, not more than 24 halogen atoms, and not more than 15 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
carbon atom 9 carries a moiety defined as for R.sub.A4I above.

5. A compound of claim 4 wherein carbons 13 and 14 of P.sub.1I carry a substituted or unsubstituted cyclopropyl ring, forming P.sub.1IN: ##STR63## wherein the R.sub.A5I and R.sub.A6I moieties are independently selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which, taken together, contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur.

6. A compound of claim 5 wherein carbon 2 Of P.sub.1IN carries a methyl group, J.sup.1 is hydroxy, J.sup.2 is hydrogen, carbon 11 carries a methyl group in the.alpha. configuration, carbon 14 carries a hydrogen in the.alpha. configuration and R.sub.A5I, and R.sub.A6I are both methyl, forming P.sub.1INL: ##STR64##

7. A compound of claim 6 selected from the group consisting of: (i) 6-des(hydroxymethyl)-6-carboxyingenol;

(ii) 6-des(hydroxymethyl)-6-carboxyingenol 3-benzoate;
(iii) 6-des(hydroxymethyl)-6-carboxyingenol 3-(2',4'-difluorobenzyl)carbamate;
(iv) 6-des(hydroxymethyl)-6-chloroingenol 3-benzoate;
(v) 6-des(hydroxymethyl)-6-chloroingenol 3-(2',4'-difluorobenzyl)carbamate;
(vi) 20-deoxy-20-azidoingenol 3-(2',4'-difluorobenzyl)carbamate;
(vii) ingenol 20-methylcarbamate;
(viii) 9-deoxy-9-butylideneingenol 20-methylthiocarbamate;
(ix) ingenol 3-benzoate 20-acetonyl ether;
(x) ingenol 3-biphenylcarbamate 20-acetonyl ether;
(xi) 20-O-(4'-hydroxyphenoxy)carbonylingenol 3-benzoate; and
(xii) 20-O-(4'-hydroxyphenoxv)carbonylingenol 3-(2',4'-difluorophenylcarbamate.

8. A compound of claim 3 wherein carbons 13 and 14 of P.sub.1R carry a substituted or unsubstituted cyclopropyl ring, forming P.sub.1P ##STR65## wherein the R.sub.A5 and R.sub.A6 moieties are independently selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which, taken together, contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur.

9. A compound of claim 8 wherein carbon 2 of P.sub.1P carries a methyl group, J.sup.1 is hydroxy, carbon 9 carries a hydroxy group in the.alpha. configuration, carbons 10 and 14 carry hydrogens in the.alpha. configuration, carbon 11 carries a methyl group in the.alpha. configuration and R.sub.A5 and R.sub.A6 are both methyl, forming P.sub.1PP: ##STR66## 10.

11. A compound of claim 3 wherein an orthoester structure is bonded to P.sub.1R via one orthoester oxygen atom in the.alpha. configuration to carbon 9 and via two orthoester oxygen atoms in the u configuration to any two of carbons 12-14, forming P.sub.1RR ##STR67## wherein R.sub.A7 represents hydrogen, halogen or a straight chain or branched chain, cyclic or acyclic, satured or unsaturated or aromatic carbon- and/or heteroatom-containing group, the group optionally completing 1 additional ring to carbon 1, which group includes not more than 30 carbon atoms, not more than 16 halogen atoms, and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur.

12. A compound of claim 11 wherein carbon 2 of P.sub.1RR carries a methyl group, J.sup.1 is hydroxy, J.sup.2 is hydrogen, carbon 10 carries a hydrogen atom in the.alpha. configuration, carbon 11 carries a methyl group in the a configuration, carbon 13 carries an isopropenyl group and said orthoester structure is bonded to carbons 9, 13 and 14, forming P.sub.1RRR ##STR68##

15. A composition consisting of:

a physiologically acceptable pharmaceutical carrier; and
a compound, in a quantity of between about 0.001-1000 mg per unit dosage, of the formula:
wherein P.sub.1 is a moiety of the formula: ##STR70## in the form of an individual isomer, an isomer mixture, a racemate or optical antipode, or a pharmaceutically acceptable salt thereof,
wherein A.sup.1 and A.sup.2 may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing substituent having not more than 34 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur; or,
A.sup.1 and A.sup.2 taken together may complete a 5- or 6-membered, saturated or unsaturated, carbocyclic or heterocyclic ring, optionally substituted by one or more halogens and/or by 1-8 straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing groups, which groups may form up to two additional rings by connections among themselves and/or to J.sup.1 or A.sup.4 and which halogen(s) and groups, taken together, contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
A.sup.3 is a three atom chain which carries S.sub.x E.sub.1 and completes a 7-membered saturated or unsaturated carbocyclic ring substituted by 0-5 substituents independently selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which groups may form up to two additional rings by connections to S.sub.4 E.sub.1, taken together, and/or J.sup.1 and which halogens and groups, taken together, excluding S.sub.x E.sub.1, contain not more than 12 carbon atoms, not more than 8 halogen atoms, and not more than 5 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur; provided that, including S.sub.x E.sub.1, the middle carbon atom of A.sup.3 is not substituted by hydroxymethyl or hydroxyethyl;
A.sup.4 is a four atom chain which completes a 6- or 7-membered carbocyclic or heterocyclic ring connected in the.beta. configuration to either carbon atom 9 or 10, optionally substituted by one or more halogens and/or by 1-8 straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing groups, the group or groups optionally completing 1-3 additional rings through bonds among themselves and/or 1-5 additional rings by connected to A.sup.1, A.sup.2, a ring formed by A.sup.1 and A.sup.2 together, and/or a bond to carbon atom 9, which halogen(s) and groups, taken together, include not more than 50 carbon atoms, not more than 24 halogen atoms, and not more than 15 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur; and,
carbon atom 9 may be optionally substituted by 1-2 halogens and/or by 1-2 straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing groups, which may be bound to carbon atom 9 by a single or double bond and may complete up to three additional rings when taken together with groups on A.sup.4 and/or on A.sup.3 and which halogen(s) and groups, taken together, include not more than 12 carbon atoms, not more than 8 halogen atoms, and not more than 5 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
J.sup.1 may be selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, amino, mono- or di(lower-alkyl)amino, methyl, ethyl, vinyl, ethynyl, propargyl, cyano, methoxy, ethoxy, trifluoromethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, acetoxy, propanoyloxy, acetyl, propanoyl, hydroxyacetyl, 2-hydroxypropanoyloxy, 3-hydroxypropanoyl, acetamido, propanamido, hydroxyacetamido, 2-hydroxypropanamido and 3-hydroxypropanamido (each of which must be situated in the.beta. configuration), or J.sup.1 by connections to A.sup.1, A.sup.2, A.sup.3 or a ring formed by A.sup.1 together with A.sup.2, may complete a 3- to 7-membered substituted or unsubstituted carbocyclic or heterocyclic ring, the substituents of which contain not more than 15 carbon atoms, not more than 10 halogens, and not more than 8 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
J.sup.2 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, allyl, propargyl, n-propyl and isopropyl;
provided that, if A.sup.1 and A.sup.2 are not linked to form a ring, A.sup.4 must carry a cyclopropyl at positions 13 and 14; provided further that the total P.sub.1 ring skeleton may not comprise any of the following six minimum carbon frameworks, which are derived from various homo-, nor- and homo-nor-steroids, with or without additional ring(s) appended: ##STR71## and, provided that, when P.sub.1 has the 19-carbon 20-nor-tigliane, 20-nor-ingenane or 20-nor-daphnane skeleton, S.sub.x E.sub.1, taken together and bonded to carbon 6, may not comprise a methyl group;
wherein S.sub.x is selected from the group consisting of S.sub.B, S.sub.2, S.sub.3, S.sub.4, S.sub.5 and S.sub.6;
wherein S.sub.B is a single or double bond;
wherein S.sub.2 is a chain of atoms of the formula: ##STR72## wherein h, i, k, m, p, and q may be independently be from 0 to 3;
j and n may independently be 0 or 1;
if j and n are both 1 and l is 0, then the sum of (k+m) must be at least 1;
if n is 1 and o is 0, then the sum of (p+q) must be at least 1;
the sum of (l+o) is 1-3;
and the sum of (h+i+j+k+2l+m+n+2o+p+q) is at least 1 but not more than 12;
wherein S.sub.3 is a chain of atoms of the formula: ##STR73## wherein r, s, u, y, a', and b' may independently be from 0 to 3;
the sum of (t+z) is 0 or 1;
the sum of (v+w+x) is 1;
the sum of (y+z+a'+b') is at least 1;
the sum of (r+s+2t+u+2v+3w+4x+y+2z+a'+b') is at least 1 but not than 12;
wherein S.sub.4 is a chain of atoms defined by: ##STR74## wherein c', d', e', h', and i' may independently be from 0 to 3;
the sum of (f'+g') must be 1 or 2;
f' and g' may independently be 0 or 1;
the sum of (c'+d'+e'+f'+g'+h'+i') is at least 1 but not more than 12;
wherein S.sub.5 is a chain of atoms defined by: ##STR75## wherein j', k', m', q', and s' may independently be from 0 to 3;
l' and r' may each be 0 or 1, but the sum of (l'+r') must be 1 or 2;
n' and p' may each be 0 or 1, but the sum of (n'+p') must be 0 or 1;
the value of o' may be 0-2;
if the sum of (n'+p') is 1 and l' is 0, then q' must be at least 1;
if the sum of (n'+p') is 1 and r' is 0, then m' must be at least 1;
the sum of (j'+k'+l'+m'+n'+o'+p'+q'+r'+s') is at least 1 but not more than 12;
wherein S.sub.6 is a chain of atoms defines by: ##STR76## wherein u', v', w', x', y', z', and m' may each be 0 or 1;
t' and a' may each independently be 0-6;
the sum of (t'+u'+v'+2w'+x'+2y'+z'+a") must be 0-8;
b", d", e", f", h", j", k" and n" may each independently be 0 or 1;
c", g", i", and l" may each independently be 0-3;
if d" and j" are both 1, then the sum of (g"+i") must be at least 1;
if either j" or k" is 1, then l" must be at least 1;
if b" is 1, then the sum of (c"+g"+h"+i"+l") must be at least 1;
if d" is 1, then the sum of (g"+h"+i"+l") must be at least 1;
the sum of (t'+u'+v'+2w'+x'+2y'+z'+a"+b"+c"+d"+e"+2f"+g"+2h"+i"+j"+k"+l") must be 0-4;
if m" is zero, R.sub.6.sup.3 or R.sub.6.sup.4 may optionally comprise an additional bond, thereby completing an unsaturated linkage to G.sup.2;
if n" and b" are zero, R.sub.6.sup.5 or R.sub.6.sup.6 may optionally comprise an additional bond, thereby completing an unsaturated linkage to G.sup.2;
one of the substituents R.sub.6.sup.1 -R.sub.6.sup.4 and/or one of the substituents R.sub.6.sup.5 -R.sub.6.sup.12 may optionally comprise the same or different values of G.sup.1, as defined below;
wherein, for S.sub.2 -S.sub.6, R.sub.2.sup.1 through R.sub.2.sup.12 may independently be selected from the group consisting of hydrogen, halogen and a saturated or singly or multiply unsaturated, straight or branched acyclic substituent containing not more than 20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, silicon, boron, selenium, arsenic and phosphorus, such that for any substituent the oxygen, nitrogen, sulfur, silicon and/or phosphorus atoms must be situated in functional groups selected from the group consisting of hydroxy, amino, hydroxylamine, tertiary amine oxide, Schiff's base, hydrazine, thiol, nitro, oxime, azide, ether, acetal, ketal, thioether, aldehyde, keto, hydrazone, carboxy, mercaptocarbonyl, mercaptothionocarbonyl, sulfonate, sulfonyl, sulfoxide, phosphate, phosphonate, phosphate ester, phosphonate ester, phosphine, phosphine oxide, thionophosphine, phosphite, phosphonium, phosphorothioate, thionophosphate ester, thiophosphonate, thionophosphonate ester, silane, silanol, silanediol, fluorinated silane, ester, amide, cyano, hydrazide, carbonate, carbamate, urea, isourea, carboxamidine, imidate, guanidine, thioester, thioamide, thiocarbonate, thiocarbamate, thiourea, nitroguanidine, cyanoguanidine and xanthate;
one substituent selected from the group consisting of R.sub.2.sup.1, R.sub.2.sup.2, R.sub.3.sup.1, R.sub.3.sup.2, R.sub.4.sup.1, R.sub.4.sup.2, R.sub.5.sup.1, R.sub.5.sup.2, R.sub.6.sup.1 and R.sub.6.sup.2 may optionally comprise an additional bond, thereby completing an unsaturated linkage to P.sub.1;
one or two of the substituents R.sub.2.sup.1 -R.sub.5.sup.12 may optionally comprise the same or different values of G.sup.1, as defined below;
one substituent selected from the group consisting of R.sub.2.sup.11, R.sub.2.sup.12, R.sub.3.sup.11, R.sub.3.sup.12, R.sub.4.sup.11, R.sub.4.sup.12, R.sub.5.sup.11, R.sub.5.sup.12, R.sub.6.sup.11 and R.sub.6.sup.12 may optionally comprise an additional bond, thereby completing an unsaturated linkage to E.sub.1;
one of the substituents R.sub.2.sup.1 -R.sub.6.sup.12 may be linked to either the atom in P.sub.1 that carries the S.sub.x chain or to an atom in P.sub.1 adjacent thereto, to form a saturated or unsaturated or aromatic, carbocyclic or heterocyclic 4-8 membered ring containing 0-4 identical or different hetero ring members selected from the group consisting of --O--, --S--, --S(O)--, --S(O).sub.2 --, --C(O)--, --NH-- and.dbd.N--, the ring being optionally substituted by 1-8 identical or different substituents selected from the group consisting of halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totaling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
provided that, for any given S.sub.2, S.sub.3, S.sub.4, S.sub.5 or S.sub.6, but excluding P.sub.1 and E.sub.1: the total of carbon atoms is 25 or less; the total of halogen atoms is 16 or less; the total of oxygen atoms is 6 or less; the total of nitrogen atoms is 4 or less; the sulfur, silicon, boron and phosphorus atoms each total 3 or less; the arsenic and selenium atoms each total 1 or less; and the total of oxygen, nitrogen, silicon, boron, arsenic, phosphorus, selenium and sulfur atoms together is 8 or less; the total of OH groups is 3 or less; the total of NH.sub.2 groups is 2 or less; the total of SH groups is 2 or less; the total of OH, SH and NH2 groups, together, is 4 or less;
X, X' and X" are independently selected from the group consisting of: ##STR77## wherein R.sub.X.sup.1, R.sub.X.sup.2, R.sub.X.sup.11 and R.sub.X.sup.12 may independently be hydrogen;
R.sub.X.sup.1 through R.sub.X.sup.12 may independently be a saturated or singly or multiply unsaturated, straight or branched acyclic substituent containing 1-20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from the group consisting of oxygen, nitrogen and sulftur, such that for any substituent the oxygen atoms total 4 or less, the nitrogen atoms total 4 or less, and the sulfur atoms total 2 or less, the heteroatoms being situated in functional groups selected from the group consisting of hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, mercaptocarbonyl, mercaptothionocarbonyl, sulfonate, sulfonyl, sulfoxide, ester, amide, cyano, carbonate, carbamate, urea, isourea, carboxamidine, guanidine, thioester, thioamide, thiocarbamate, thiourea, nitroguanidine, cyanoguanidine and xanthate; wherein said functional groups are separated from the atom to which R.sub.X.sup.1 -R.sub.X.sup.12 is attached by at least two carbon atoms;
R.sub.X.sup.4, R.sub.X.sup.5, R.sub.X.sup.11 and R.sub.X.sup.12 may independently be hydroxy;
R.sub.X.sup.1 may optionally represent an additional bond, thereby completing an unsaturated linkage to P.sub.1;
one or two of the substituents R.sub.X.sup.1 -R.sub.X.sup.12 may optionally comprise the same or different values of G.sup.1, as defined below;
wherein Y and Y' are selected from the group consisting of: ##STR78## wherein R.sub.Y.sup.1 and R.sub.Y.sup.2, and R.sub.Y.sup.3 and R.sub.Y.sup.4, each pair being cis or trans relative to one another, may independently be hydrogen or a saturated or singly or multiply unsaturated, straight or branched acyclic substituent containing not more than 20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, such that for any substituent the oxygen atoms total 4 of less, the nitrogen atoms total 4 or less, and the sulfur atoms total 2 or less, the heteroatoms being situated in functional groups as defined for R.sub.X.sup.1 -R.sub.X.sup.12;
R.sub.Y.sup.1 and R.sub.Y.sup.2 may also independently be a halogen;
one or two of the substituents R.sub.Y.sup.1 -R.sub.Y.sup.4 may optionally comprise the same or different values of G.sup.1, as defined below;
one of the substituents selected from the group consisting of R.sub.X.sup.1 -R.sub.X.sup.12 and R.sub.Y.sup.1 -R.sub.Y.sup.4 may be linked to either the atom in P.sub.1 that carries the chain containing X, X', X", Y and/or Y' or to an atom in P.sub.1 adjacent thereto, to form a 4-8 membered ring defined as for the analogous R.sub.2.sup.1 -R.sub.6.sup.2 -containing ring above;
wherein
Z.sup.1 is selected from the group consisting of: ##STR79## Z.sup.2 is selected from the group consisting of: ##STR80## Z.sup.3 is selected from the group consisting of: ##STR81## Z.sup.4 and Z.sup.4' independently are: ##STR82## and Z.sup.5 and Z.sup.5' independently are selected from the group consisting of: ##STR83## wherein R.sub.Z.sup.26 may be any of the values specified for R.sub.X.sup.1 -R.sub.X.sup.12 above;
R.sub.Z.sup.18 and R.sub.Z.sup.19 may independently be selected from the group consisting of --O--, --S-- and --NR.sub.Z.sup.21 -- wherein R.sub.Z.sup.21 may be selected from the group consisting of hydrogen, C.sub.1-4 alkyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, 2-acetoxyethyl and 2-acetoxy-n-propyl;
R.sub.Z.sup.17 and R.sub.Z.sup.20 may independently be hydrogen or a substituent selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, phenoxy or thiophenoxy wherein each phenyl group may optionally be substituted by moieties selected from the group consisting of methyl, hydroxy, hydroxymethyl, thiol, carboxy, carboxymethyl, amino, methoxy, halogen and nitro, and amino optionally mono- or disubstituted by C.sub.1-4 alkyl or monosubstituted by a substituent selected from the group consisting of cyano, nitro and phenyl (optionally substituted by moieties selected from the group consisting of halogen, hydroxy, hydroxymethyl, thiol, carboxy, carboxymethyl, amino and nitro);
R.sub.Z.sup.1 -R.sub.Z.sup.6, R.sub.Z.sup.22 -R.sub.Z.sup.25 and R.sub.Z.sup.27 -R.sub.Z.sup.30 may independently be hydrogen or a saturated or unsaturated substituent selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 halogenated alkyl, cyclohexyl and phenyl or benzyl wherein each phenyl group may optionally be substituted by moieties selected from the group consisting of methyl, ethyl, hydroxy, hydroxymethyl, thiol, carboxy, carboxymethyl, amino, methoxy, nitro, cyano, trifluoromethyl and halogen;
R.sub.Z.sup.1 -R.sub.Z.sup.4, R.sub.Z.sup.7, R.sub.Z.sup.10, R.sub.Z.sup.12, R.sub.Z.sup.13 and R.sub.Z.sup.27 -R.sub.Z.sup.30 may also be independently selected from the group consisting of C.sub.1-6 acyl, C.sub.1-6 halogenated acyl, C.sub.2-6 monohydroxyacyl and C.sub.2-6 hydroxyalkyl;
R.sub.Z.sup.5 and R.sub.Z.sup.6 may also be independently selected from the group consisting of C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxy and C.sub.1-6 hydroxyalkoxy;
R.sub.Z.sup.8, R.sub.Z.sup.9, R.sub.Z.sup.23 and R.sub.Z.sup.24 may also independently be C.sub.2-6 hydroxyalkyl;
one of the substituents R.sub.Z.sup.1 -R.sub.Z.sub.17, R.sub.Z.sup.20, R.sub.Z.sup.21, R.sub.Z.sup.22 and R.sub.Z.sup.25 may be linked to either the atom in P.sub.1 that carries the chain containing Z.sup.1, Z.sup.2 or Z.sup.3 or to an atom in P.sub.1 adjacent thereto, to form a saturated or unsaturated or aromatic, carbocyclic or heterocyclic 4-8 membered ring containing 0-4 identical or different hetero ring members selected from the group consisting of O, S,.dbd.N-- and NH, the ring being optionally substituted on its carbon and/or NH members by 1-8 identical or different substituents selected from the group consisting of halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totaling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
R.sub.Z.sup.26 may comprise G.sup.1 as defined below, and/or an optional ring may be formed between R.sub.Z.sup.26 and P.sub.1 as described above for R.sub.2.sup.1 -R.sub.6.sup.12;
R.sub.Z.sup.1, R.sub.Z.sup.4, R.sub.Z.sup.7, R.sub.Z.sup.26 or R.sub.Z.sup.27 may comprise an additional bond, thereby completing an unsaturated linkage to P.sub.1;
only one of the substituents R.sub.Z.sup.1 -R.sub.Z.sup.25 may be substituted or unsubstituted phenyl or benzyl;
wherein M and M' are independently selected from the group consisting of: ##STR84## wherein R.sub.M.sup.1 and R.sub.M.sup.2 may independently be hydrogen or a saturated or singly or multiply unsaturated, straight or branched acyclic substituent containing 1-20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, in which the oxygen atoms total 4 or less, the nitrogen atoms total 4 or less, and the sulfur atoms total 2 or less, the heteroatoms being situated in functional groups selected from the group consisting of hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, nitroguanidine and cyanoguanidine;
R.sub.M.sup.1 may optionally comprise an additional bond, thereby completing an unsaturated linkage to P.sub.1;
R.sub.M.sup.1 or R.sub.M.sup.2 may optionally comprise the same or different values of G.sup.1, as defined below;
R.sub.M.sup.1 or R.sub.M.sup.2 may be linked to either the atom in P.sub.1 that carries the chain containing M and/or M' or to an atom in P.sub.1 adjacent thereto, to form a 4-8 membered ring defined as for the analogous R.sub.2.sup.1 -R.sub.6.sup.12 -containing ring above;
wherein Q, Q' and Q'" are independently selected from the group consisting of:
.dbd.O.dbd.S.dbd.N--R.sub.Q.sup.1 and.dbd.N--O--R.sub.Q.sup.2
and wherein Q" is selected from the group consisting of:.dbd.O.dbd.N--R.sub.Q.sup.1 and.dbd.N--O--R.sub.Q.sup.2
wherein R.sub.Q.sup.1 and R.sub.Q.sup.2 may independently be hydrogen or a saturated or singly or multiply unsaturated, straight or branched acyclic substituent containing 1-20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, in which the oxygen atoms total 4 or less, the nitrogen atoms total 4 or less, and the sulfur atoms total 2 or less, the heteroatoms being situated in functional groups selected from the group consisting of hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, nitroguanidine and cyanoguanidine;
R.sub.Q.sup.1 and/or R.sub.Q.sup.2 may optionally comprise the same or different values of G.sup.1, as defined below;
R.sub.Q.sup.1 may be linked to either the atom in P.sub.1 that carries the chain containing Q and/or Q' or to an atom in P.sub.1 adjacent thereto, to form a 4-8 membered ring defined as for R.sub.2.sup.1 -R.sub.6.sup.12 -containing ring above,
wherein R.sup.Q -R.sup.Q'" are independently selected from the group consisting of: ##STR85## wherein R.sub.Q.sup.3 and R.sub.Q.sup.4 may independently be selected from the group consisting of halogen, hydrogen and a saturated or singly or multiply unsaturated, straight or branched acyclic substituent containing 1-20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, in which the oxygen atoms total 4 or less, the nitrogen atoms total 4 or less, and the sulfur atoms total 2 or less, the heteroatoms being situated in functional groups selected from the group consisting of hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, nitroguanidine and cyanoguanidine;
R.sub.Q.sup.3 and/or R.sub.Q.sup.4 may optionally comprise the same or different values of G.sup.1, as defined below;
one of R.sub.Q.sup.3 and R.sub.Q.sup.4 may be linked to either the atom in P.sub.1 bonded to the chain that carries R.sup.Q or to an atom in P.sub.1 adjacent thereto, to form a 4-8 membered ring defined as for R.sub.2.sup.1 -R.sub.6.sup.12 -containing ring above;
wherein G.sup.1 and G.sup.2 independently comprise a group containing 1-3 fused or separate, saturated or unsaturated or aromatic, carbocyclic or heterocyclic 4-8 membered rings, each ring containing 0-4 identical or different hetero ring members selected from the group consisting of --O--, --S--, --S(O)--, --S(O).sub.2 --, --C(O)--, --NH-- and.dbd.N--, each ring being optionally substituted on its carbon and/or NH members by 1-8 identical or different substituents, selected from the group consisting of halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totaling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
wherein for G.sup.1 the optional second and third rings may be fused to the first ring and/or to one another or may be separate rings connected to one another and/or to the atom bearing G.sup.1 by a single or double bond or by an intervening substituted or unsubstituted, linear or branched, saturated or unsaturated chain containing not more than 8 carbon atoms, not more than 8 halogens, and not more than 4 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, boron, arsenic, phosphorus, selenium and sulfur;
and wherein for G.sup.2 the first ring is singly or doubly bonded to P.sub.1 or to a component atom of the S.sub.6 chain connecting P.sub.1 and G.sup.2, and the optional second and third rings may be fised to the first ring or to one another or may be separate rings connected to one another and/or to the first ring by single or double bonds or by an intervening substituted or unsubstituted, linear or branched, saturated or unsaturated chain containing not more than 8 carbon atoms, not more than 8 halogens, and not more than 4 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, boron, arsenic, phosphorus, selenium and sulfur;
wherein E.sub.1 is selected from the group consisting of.dbd.O,.dbd.S,.dbd.NH,.dbd.NOR.sub.E.sup.8 wherein R.sub.E.sup.8 is hydrogen or a C.sub.1 -C.sub.8 normal or branched alkyl radical,.dbd.N--NH.sub.2, hydrogen, halogen, --OH, --SH, --NH.sub.2, --NH--NH.sub.2,--N.sub.3, --CN, --NO, --NO.sub.2, --NHOH, --ONH.sub.2, ##STR86## wherein T.sup.1 is selected from the group consisting of --O--, --S-- and --NH--;
T.sup.2 is selected from the group consisting of.dbd.O,.dbd.S and.dbd.N--R.sub.E.sup.6 wherein R.sub.E.sup.6 is selected from the group consisting of hydrogen, hydroxy, cyano and nitro;
T.sup.2' is selected from the group consisting of.dbd.O and.dbd.S;
T.sup.3, T.sup.4 and T.sup.4' may independently be selected from the group consisting of --OH, --NH.sub.2, --SH, --N.sub.3, --NH--NH.sub.2 and --NH--OR.sub.E.sup.7 wherein R.sub.E.sup.7 is selected from the group consisting of hydrogen, C.sub.1-3 alkyl and C.sub.1-3 acyl;
T.sup.3 may also be hydrogen or halogen;
T.sup.5 is selected from the group consisting of hydrogen, halogen and hydroxy;
T.sup.5 and T.sup.5' are independently hydrogen or hydroxy;
R.sub.E.sup.1 is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, nitroso, cyano, azide, --NH.sub.2, --NH--OH, --SH, --O--NH.sub.2, --NH--NH.sub.2, --T.sup.1 --C(.dbd.T.sup.2)--T.sup.3, --C(.dbd.T.sup.2)--T.sup.3, --SiT.sup.5 T.sup.5' T.sup.5", --T.sup.1 --S(.dbd.O)(.dbd.T.sup.2)--T.sup.4, --S(.dbd.O)(.dbd.T.sup.2)--T.sup.4, --T.sup.1 --P(--T.sup.4)--T.sup.4', --P(--T.sup.4)--T.sup.4', --T.sup.1 --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4 and --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4;
R.sub.E.sup.2 and R.sub.E.sup.3 may individually be selected from the group consisting of hydrogen, --C(.dbd.T.sup.2)--T.sup.3, cyano, nitro, azide, halogen and a C.sub.1 -C.sub.15 straight or branched chain, saturated or unsaturated or aromatic-containing alkyl moiety optionally containing not more than 10 halogen atoms and not more than 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
if R.sub.E.sup.1 is cyano or --C(.dbd.T.sup.2)--T.sup.3, then R.sub.E.sup.2 or R.sub.E.sup.3 may optionally be selected from the group consisting of --SiT.sup.5 T.sup.5' T.sup.5", --T.sup.1 --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4 and --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4; and
R.sub.E.sup.4 and R.sub.E.sup.5 are individually selected from the group consisting of hydrogen, halogen, cyano, nitro, --C(.dbd.T.sup.2)--T.sup.3, --T.sup.1 --C(.dbd.T.sup.2)--T.sup.3, --CR.sub.E.sup.1 R.sub.E.sup.2 R.sub.E.sup.3, --SiT.sup.5 T.sup.5' T.sup.5", --S(.dbd.O)(.dbd.T.sup.2)--T.sup.4 and --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4.

16. A composition of claim 15 wherein S.sub.x E.sub.1 of the compound, taken together, is selected from the group consisting of:

(i) a moiety selected from the group consisting of dihalomethyl, trihalomethyl, --N.sub.3, --NH.sub.2, --CN, --COOH, --CH.dbd.CHCOOH, --C.dbd.--CCOOH, --CSSH, --COSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH, --CH.dbd.NOH, --CH.dbd.CHR.sub.a.sup.a, --C.tbd.C--R.sub.a.sup.a, --CH.sub.2 C.dbd.C--R.sub.a.sup.a, --Si(CH.sub.3).sub.2 OH, --Si(OH).sub.2 CH.sub.3, --Si(CH.sub.3).sub.2 F, --Si(CH.sub.3).sub.2 R.sub.a.sup.a, --CH.sub.2 Si(CH.sub.3).sub.2 R.sup.a and.dbd.CHR.sub.a.sup.a; and
(ii) --CH.sub.2 -- or --CH(CH.sub.3)--, to either of which is bonded a moiety selected from the group consisting of --R.sub.a.sup.a, --F, --N.sub.3, --NH.sub.2, --CN, --COOH, --COSH, --CSSH, --Si(CH.sub.3).sub.2 OH, --Si(OH).sub.2 CH.sub.3, --Si(CH.sub.3).sub.2 F, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(R.sub.a.sup.a)OH, --P(.dbd.S)(R.sub.a.sup.a)OH, --P(.dbd.O)(OR.sub.a.sup.a)OH, ---P(.dbd.S)(OR.sub.a.sup.a)OH, the o-, m- or p-isomer of --M--C.sub.6 H.sub.4 CH.sub.2 --T.sup.3, the o-, m- or p-isomer of --C.sub.6 H.sub.4 CH.sub.2 --T.sup.3, --M--C(.dbd.T.sup.2)--M'--R.sub.a.sup.a, --OCH.sub.2 C(.dbd.O)CH.sub.3, --OCH.sub.2 C(.dbd.NOH)CH.sub.3, the o-, m- or p-isomer of --M--C(.dbd.T.sup.2)--M'--C.sub.6 H.sub.4 --T.sup.3, the o-, m- or p-isomer of --M--C(.dbd.T.sup.2)--M'--C.sub.6 H.sub.4 CH.sub.2 --T.sup.3 and -imidazol-2-yl;

17. A composition of claim 15 wherein P.sub.1 is P.sub.1R: ##STR87## wherein carbons 1 and 2 or carbons 2 and 3 may be joined by a double bond; carbons 5 and 6 or carbons 6 and 7 may be joined by a double bond;

S.sub.x E.sub.1, taken together, may be bonded to carbon 5, 6 or 7;
R.sub.A1 represents not more than 6 identical or different moieties bonded independently via single and/or double bonds to carbons 1, 2 and/or 3, which moieties may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which groups may form up to two additional rings by connections among themselves and/or to J.sup.1 or R.sub.A4 and which halogen(s) and groups, taken together, contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
R.sub.A3 represents not more than 5 identical or different moieties bonded independently via single and/or double bonds to carbons 5, 6 and/or 7, which moieties may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which groups may form up to two additional rings by connection to S.sub.x E.sub.1, taken together, and/or J.sup.1 and which halogens and groups, taken together, contain not more than 12 carbon atoms, not more than 8 halogen atoms, and not more than 5 heteroatoms selected from the group selected from oxygen, nitrogen, silicon, phosphorus and sulfur; and
R.sub.A4 represents not more than 9 identical or different moieties bonded independently via single or double bonds to carbons 9, 11, 12, 13 and/or 14, which moieties may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, the group or groups optionally completing 1-3 additional rings through bonds among themselves and/or 1-5 additional rings by connections to the 5-membered ring and its substituent(s), R.sub.A1, which halogen and groups, taken together, include not more than 50 carbon atoms, not more than 24 halogen atoms, and not more than 15 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur.

18. A composition of claim 17 wherein carbons 13 and 14 of P.sub.1R carry a substituted or unsubstituted cyclopropyl ring, forming P.sub.1P ##STR88## wherein the R.sub.A5 and R.sub.A6 moieties are independently selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which, taken together, contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur.

19. A composition of claim 18 wherein carbon 2 of P.sub.1P carries a methyl group, J.sup.1 is hydroxy, carbon 9 carries a hydroxy group in the.alpha. configuration, carbons 10 and 14 carry hydrogens in the.alpha. configuration, carbon 11 carries a methyl group in the.alpha. configuration and R.sub.A5 and R.sub.A6 are both methyl, forming P.sub.1PP: ##STR89## 20.

21. A composition of claim 17 wherein an orthoester structure is bonded to P.sub.1R via one orthoester oxygen atom in the.alpha. configuration to carbon 9 and via two orthoester oxygen atoms in the.alpha. configuration to any two of carbons 12-14, forming P.sub.1RR ##STR90## wherein R.sub.A7 represents hydrogen, halogen or a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, the group optionally completing 1 additional ring to carbon 1, which group includes not more than 30 carbon atoms, not more than 16 halogen atoms, and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur.

22. A composition of claim 21 wherein carbon 2 of P.sub.1RR carries a methyl group, J.sup.1 is hydroxy, J.sup.2 is hydrogen, carbon 10 carries a hydrogen atom in the.alpha. configuration, carbon 11 carries a methyl group in the.alpha. configuration, carbon 13 carries an isopropenyl group and said orthoester structure is bonded to carbons 9, 13 and 14, forming P.sub.1RRR ##STR91##

24. A composition of claim 15 wherein P.sub.1 is P.sub.1I: ##STR92## wherein carbons 1 and 2 or carbons 2 and 3 may be joined by a double bond; carbons 5 and 6 or carbons 6 and 7 may be joined by a double bond;

S.sub.x E.sub.1, taken together, may be bonded to carbon 5, 6 or 7;
R.sub.A2I represents not more than 6 identical or different moieties bonded independently via single and/or double bonds to carbons 1, 2 and/or 3, which moieties may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which groups may form up to two additional rings by connections among themselves and/or to J.sup.1 or R.sub.A4I and which halogens and groups, taken together, contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
R.sub.A3I represents not more than 5 identical or different moieties bonded independently via single and/or double bonds to carbons 5, 6 and/or 7, which moieties may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which groups may form up to two additional rings by connections to S.sub.x E.sub.1, taken together, and/or J.sup.1 and which halogens and groups, taken together, contain not more than 12 carbon atoms, not more than 8 halogen atoms, and not more than 5 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
R.sub.A4I represents not more than 8 identical or different moieties bonded independently via single or double bonds to carbons 11, 12, 13 and/or 14, which moieties may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, the group or groups optionally completing 1-3 additional rings through bonds among themselves and/or 1-5 additional rings by connections to the 5-membered ring and its substituent(s), R.sub.A2I, which halogen and groups, taken together, include not more than 50 carbon atoms, not more than 24 halogen atoms, and not more than 15 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
carbon atom 9 carries a moiety defined as for R.sub.A4I above.

25. A composition of claim 24 wherein carbons 13 and 14 of P.sub.1I carry a substituted or unsubstituted cyclopropyl ring, forming P.sub.1IN: ##STR93## wherein the R.sub.A5I and R.sub.A6I moieties are independently selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group, which, taken together, contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur.

26. A composition of claim 25 wherein carbon 2 of P.sub.1IN carries a methyl group, J.sup.1 is hydroxy, J.sup.2 is hydrogen, carbon 11 carries a methyl group in the.alpha. configuration, carbon 14 carries a hydrogen in the.alpha. configuration and R.sub.A5I and R.sub.A6I are both methyl, forming P.sub.1INL: ##STR94##

27. A composition of claim 26 wherein the compound is selected from the group consisting of: (i) 6-des(hydroxymethyl)-6-carboxyingenol;

(ii) 6-des(hydroxymethyl)-6-carboxyingenol 3-benzoate;
(iii) 6-des(hydroxymethyl)-6-carboxyingenol 3-(2',4'-difluorobenzyl)carbamate;
(iv) 6-des(hydroxymethyl)-6-chloroingenol 3-benzoate;
(v) 6-des(hydroxymethyl)-6-chloroingenol 3-(2',4'-difluorobenzyl)carbamate;
(vi) 20-deoxy-20-azidoingenol 3-(2',4'-difluorobenzyl)carbamate;
(vii) ingenol 20-methylcarbamate;
(viii) 9-deoxy-9-butylideneingenol 20-methylthiocarbamate;
(ix) ingenol 3-benzoate 20-acetonyl ether;
(x) ingenol 3-biphenylcarbamate 20-acetonyl ether;
(xi) 20-O-(4'-hydroxyphenoxy)carbonylingenol 3-benzoate; and
(xii) 20-O-(4'-hydroxyphenoxy)carbonylingenol 3-(2',4'-difluorophenylcarbamate.

29. A composition of claim 28 wherein the compound is a diterpene phorboid-type pharmacological antagonist of the diacylglycerol binding site of protein kinase C.

30. A composition of claim 28 wherein the compound is a noninflammatory diterpene phorboid-type agonist of the diacylglycerol binding site of protein kinase C.

31. A composition of claim 28 wherein the compound is a diterpene phorboid-type pharmacological antagonist of a diacylglycerol binding site.

32. A composition of claim 28 wherein the compound is a noninflammatory diterpene phorboid-type agonist of the diacylglycerol binding site.

33. A method of treating inflammation in a mammal in need of anti-inflammatory or anti-psoriatic treatment comprising the step of administering a composition of claim 15 to said mammal.

34. A method of treating inflammation in a mammal in need of anti-inflammatory or anti-psoriatic treatment comprising the step of administering a composition of claim 19 to said mammal.

35. A method of treating inflammation in a mammal in need of anti-inflammatory or anti-psoriatic treatment comprising the step of administering a composition of claim 22 to said mammal.

36. A method of treating inflammation in a mammal in need of anti-inflammatory or anti-psoriatic treatment comprising the step of administering a composition of claim 26 to said mammal.

37. A method of modulating protein kinase C activity comprising the step of contacting protein kinase C, in vitro or in vivo, with a composition of claim 15.

38. A method of modulating protein kinase C activity comprising the step of contacting protein kinase C, in vitro or in vivo, with a composition of claim 19.

39. A method of modulating protein kinase C activity comprising the step of contacting protein kinase C, in vitro or in vivo, with a composition of claim 22.

40. A method of modulating protein kinase C activity comprising the step of contacting protein kinase C, in vitro or in vivo, with a composition of claim 36.

41. A method of modulating protein kinase C activity comprising the step of contacting protein kinase C, in vitro or in vivo, with a composition of claim 28.

42. A method for treating a mammal infected with a virus which comprises administering to a mammal in need of such treatment an antivirally effective quantity of a composition of claim 15; provided that, said composition does not include compounds wherein S.sub.x E.sub.1, taken together, is selected from the group consisting of:

(i) a moiety selected from the group consisting of --COOH, --CH.dbd.CHCOOH, --C.tbd.--CCOOH, --CSSH, --COSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH; and
(ii) --CH.sub.2 -- or --CH(CH.sub.3)--, to either of which is bonded a moiety selected from the group consisting of --COOH, --COSH, --CSSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(R.sub.a.sup.a)OH, --P(.dbd.S)(R.sub.a.sup.a)OH, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH;

43. A method for treating a mammal infected with a virus which comprises administering to a mammal in need of such treatment an antivirally effective quantity of a composition of claim 19; provided that, said composition does not include compounds wherein S.sub.x E.sub.1, taken together, is selected from the group consisting of:

(i) a moiety selected from the group consisting of --COOH, --CH.dbd.CHCOOH, --C.tbd.CCOOH, --CSSH, --COSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH; and
(ii) --CH.sub.2 -- or --CH(CH.sub.3)--, to either of which is bonded a moiety selected from the group consisting of --COOH, --COSH, --CSSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(R.sub.a.sup.a)OH, --P(.dbd.S)(R.sub.a.sup.a)OH, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH;

44. A method for treating a mammal infected with a virus which comprises administering to a mammal in need of such treatment an antivirally effective quantity of a composition of claim 22; provided that, said composition does not include compounds wherein S.sub.x E.sub.1, taken together, is selected from the group consisting of:

(i) a moiety selected from the group consisting of --COOH, --CH.dbd.CHCOOH, --C.tbd.CCOOH, --CSSH, --COSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH; and
(ii) --CH.sub.2 -- or --CH(CH.sub.3)--, to either of which is bonded a moiety selected from the group consisting of --COOH, --COSH, --CSSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(R.sub.a.sup.a)OH, -P(.dbd.S)(R.sub.a.sup.a)OH, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH;

45. A method for treating a mammal infected with a virus which comprises administering to a mammal in need of such treatment an antivirally effective quantity of a composition of claim 26; provided that, said composition does not include compounds wherein S.sub.x E.sub.1, taken together, is selected from the group consisting of

(i) a moiety selected from the group consisting of --COOH, --CH.dbd.CHCOOH, --C.tbd.CCOOH, --CSSH, --COSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH; and
(ii) --CH.sub.2 -- or --CH(CH.sub.3)--, to either of which is bonded a moiety selected from the group consisting of --COOH, --COSH, --CSSH, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, --P(.dbd.O)(R.sub.a.sup.a)OH, -P(.dbd.S)(R.sub.a.sup.a)OH, --P(.dbd.O)(OR.sub.a.sup.a)OH, --P(.dbd.S)(OR.sub.a.sup.a)OH;

46. A method of claim 35 wherein said virus is a retrovirus.

47. A method of claim 46 wherein said retrovirus is a Human Immunodeficiency Virus.

Referenced Cited
U.S. Patent Documents
4376821 March 15, 1983 Braude
4376822 March 15, 1983 Braude
4401756 August 30, 1983 Gillis
4460685 July 17, 1984 Vilcek et al.
4560774 December 24, 1985 Petit et al.
4716179 December 29, 1987 Hecker et al.
5089517 February 18, 1992 Choi et al.
5145842 September 8, 1992 Driedger et al.
5643948 July 1, 1997 Driedger et al.
5716968 February 10, 1998 Driedger et al.
5750568 May 12, 1998 Driedger et al.
Foreign Patent Documents
87/07599 December 1987 WOX
Other references
Patent History
Patent number: 5955501
Type: Grant
Filed: Jun 7, 1995
Date of Patent: Sep 21, 1999
Assignee: Procyon Pharmaceuticals, Inc. (Woburn, MA)
Inventors: Paul E. Driedger (Boston, MA), James Quick (Lexington, MA)
Primary Examiner: Richard L. Raymond
Law Firm: Hamilton, Brook, Smith & Reynolds, P.C.
Application Number: 8/480,191
Classifications
Current U.S. Class: Compound Contains Two Or More C(=o)o Groups Indirectly Bonded Together By Only Conalent Bonds (514/533); (c)(r)p=x(-xc) Containing (i.e., Phosphinate (x Is Chalcogen; R Is C Or H) (514/140); (cx-) (c)p=x(xh) Or (cx-) (r)p=x(xc) Containing (e.g., Phosphonate, Etc.) (x Is Chalcogen; R Is C Or H) (514/141); Polycyclo Ring System Attached By Nonionic Bonding (514/480); X-c(=x)-x Containing (e.g., Carbonic Acid Ester, Thiocarbonic Acid Ester, Etc.) (x Is Chalcogen) (514/512); Z-c(=o)-o-y, Wherein Z Contains A Benzene Ring (514/532); C(=o)o Attached Directly Through The Carbon To A Benzene Ring (514/544); Zc(=o)oy, Wherein Z Is An Acyclic Radical Bonded To The C=o By A Carbon And Y Is An Organic Radical Bonded To The Oxygen By A Carbon (514/546); Ring Is Alcohol Moiety (514/548); Z Contains An Unbroken Chain Of At Least Seven Carbon Atoms Bonded Directly To The C(=o) Group (514/552); Radical -xh Acid, Or Anhydride, Acid Halide Or Salt Thereof (x Is Chalcogen) Doai (514/553); Carboxylic Acid, Percarboxylic Acid, Or Salt Thereof (e.g., Peracetic Acid, Etc.) (514/557); Tricyclo Ring System (514/662); Benzene Ring Containing (514/717); Azides (552/1); Purine Containing (including Hydrogenated) (544/228); Boron Or Silicon Containing (544/229); Nitrogen Bonded Directly To The Carbon Of The -c(=x)x- Group (e.g., Thiocarbamates, Etc.) (558/232); Nitrogen Bonded Directly To The Benzene Ring (558/272); Nitrogen Or Chalcogen Attached Indirectly To The -o-c(=o)o- Group By Acyclic Nonionic Bonding (558/276); Plural Rings In Acid Moiety (560/27); Ring In Alcohol Moiety (560/31); Ring In Alcohol Moiety (560/32); Halogen In Acid Moiety (560/83); Rings Bonded Directly To Each Other In Acid Moiety (560/102); Additional Unsaturation In Acid Moiety (560/104); Carboxyl, Not Bonded Directly To A Ring, In Acid Moiety (560/105); Plural Rings In Alcohol Moiety (560/107); Cyclic Alcohol Moiety (560/162); Plural Rings In Alcohol Moiety (560/194); Terpene Alcohol Moiety (560/249); Polycyclo-alicyclic Ring System In Alcohol Moiety (560/256); Phosphorus Acids Or Salts Thereof (i.e., Compounds Having -xh, Wherein X Is Chalcogen, Attached Directly To Phosphorus By Nonionic Bonding And Wherein The Hydrogen May Be Replaced By A Substituted Or Unsubstituted Ammonium Or By A Group Ia Or Iia Light Metal) (562/8); Polycyclo Alicyclic Ring System Attached Directly Or Indirectly To The Sulfonate Group By Nonionic Bonding (562/100); Plural Alicyclic Rings (562/498); Polycyclo Ring System (568/632)
International Classification: A61K 31235;